Estudo do cloridrato de fenilefrina em associação com outros insumos farmacêuticos ativos: compatibilidades físico-químicas, identificação e qualificação de produtos de degradação
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2022-09-02
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Universidade Federal de Goiás
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Phenylephrine hydrochloride is a medication widely used in medicine to increase blood pressure during surgical procedures and to promote objective and subjective relief of nasal congestion in patients with the common cold. For this reason, it is largely used in fixed-dose combination medicines, associated with active pharmaceuticals ingredients (APIs) such as acetaminophen, caffeine, dexchlorpheniramine maleate, pheniramine maleate, and acetylsalicylic acid. Given the well-known chemical instability of phenylephrine hydrochloride and in order to increase the knowledge about the interactions of this API with other medications, in this thesis the results of Differential Scanning Calorimetry (DSC) and Thermogravimetry (TGA) curves of isolated APIs:
phenylephrine hydrochloride, paracetamol, caffeine, acetylsalicylic acid, dexchlorpheniramine and pheniramine maleates and the drug-drug compatibility studies under stress conditions, in solid phase, for binary mixtures containing phenylephrine hydrochloride in association with other APIs were evaluated and discussed. Furthermore, in order to obtain data on the degradation products formed from the interactions of the associations tested, the use of techniques such as high-performance liquid chromatography coupled with ultraviolet-visible detector (HPLC/UV-VIS) and with high resolution mass spectrometer (HPLC/HRMS) were employed to quantify and elucidate the structures of impurities formed in the associations tested and in products available in the local market. The genotoxic potential of these compounds was also evaluated in silico using the Genotox-iS® 3.0 toxicological prediction software. The data obtained attested that phenylephrine hydrochloride is a hygroscopic API, physically incompatible with acetylsalicylic acid and with APIs that have maleate as a counterion. The investigation of the degraded samples allowed elucidating the structures of the degradation products formed of which only compounds named in this work as I and IV are reported in the literature, however, without mention for their toxicity. The detected degradation products were qualified in silico according to the prerogatives of the The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) M7 guide, and categorized as class 5 (non-mutagenic): compounds I, II and III and class 3 (structural alert, not related to the structure of the drug substance; no mutagenicity data): compound IV. Three of the commercially available medicines tested exhibited the presence of high concentrations of Compound I.
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SILVA, A. M. Estudo do cloridrato de fenilefrina em associação com outros insumos farmacêuticos ativos: compatibilidades físico-químicas, identificação e qualificação de produtos de degradação. 2022. 300 f. Tese (Doutorado em Química) - Universidade Federal de Goiás, Goiânia, 2022.